KR100885713B1 - Systems and methods for aerosolizing pharmaceutical formulations - Google Patents

Abstract

The systems and methods of the present invention are provided for aerosolizing pharmaceutical formulations. According to one method, when trying to breathe, breathing gas is blocked from flowing to the lungs. After this, the breathing gas is allowed to flow into the lungs suddenly. At this time, the flow of respiratory gas may be used to extract the pharmaceutical formulation from the receptacle and place the pharmaceutical formulation within the flow of respiratory gas to form an aerosol.

Description

Aerosolization System and Method of Pharmaceutical Formulations {SYSTEMS AND METHODS FOR AEROSOLIZING PHARMACEUTICAL FORMULATIONS}

The present invention relates generally to the field of pharmaceutical delivery, in particular to the delivery of pharmaceutical agents to the lungs. More specifically, the present invention relates to aerosolization of pharmaceutical formulations using energy generated by inhalation of a patient.

Effective drug delivery to patients is an important aspect for all successful drug treatments, and various drug delivery techniques have been proposed. For example, the most convenient method is to deliver pills, capsules, elixirs through the oral cavity. However, oral delivery may be undesirable if the efficacy in the digestive tract decreases before many drugs are absorbed. Another technique is subcutaneous injection. The disadvantage of this solution is the low patient response. Other alternative routes of administration that have been proposed include transdermal delivery, intranasal delivery, rectal delivery, intravaginal delivery, and pulmonary delivery.

A major concern of the present invention is the pulmonary delivery technique, which relies on the patient inhaling the pharmaceutical formulation so that the active agent can be dispersed to reach the terminal (alveolar) region of the lung. Various aerosolization systems have been proposed for dispersing pharmaceutical formulations. For example, US Pat. Nos. 5,785,049 and 5,740,794, which are incorporated herein by reference, describe one example of a powder dispersion apparatus that aerosolizes a powder using a compressed gas. Other forms of aerosolization systems include MDI's (typically with drugs stored in propellants), spraying devices (aerosolizing liquids using compressed gas, which is usually air), and the like.

Another important technique in the present invention is the use of inhaled gases to disperse the pharmaceutical formulation. In this way, the patient can be provided with the energy necessary to aerosolize the pharmaceutical formulation by his inhalation. This ensures that the generation and inhalation of aerosols occur at the same time as appropriate. The use of inhalation gas by a patient can be problematic in several ways. For some pharmaceutical formulations, such as insulin, for example, it may be desirable to limit the inhalation flow rate within certain limits. For example, PCT / US99 / 04654, filed March 11, 1999, discloses delivery of insulin to the lung at a rate of less than 17 liters per minute. As another example, co-pending US patent application Ser. No. 09 / 414,384 describes a waste delivery technique that initially provides a high flow resistance and then a lower flow resistance. The entire contents of all of these references are incorporated herein by reference.

Another problem with using a patient's inhalation gas is that the inhalation flow rate can vary significantly between individuals. For example, as shown in FIG. 1, 17 random samples, measured twice a week for 4 weeks, show flow rates ranging from about 5 liters to about 35 liters per minute. Such variability can affect the ability of the pharmaceutical formulation to disperse in the gas stream, the ability to grind powdered medication, and / or the ability of the aerosolized pharmaceutical formulation to reach the lungs properly.

Accordingly, the present invention relates to a technique for regulating the flow of inhalation gas that can be used when dispersing a pharmaceutical formulation. According to one aspect of the present invention, the present invention improves the ability of a pharmaceutical formulation to be dispersed in a gas stream produced by a patient, improves the ability to grind a powdered pharmaceutical formulation, and enhances the ability of an aerosolized pharmaceutical formulation. To reach the lungs properly.

The present invention provides preferred systems and methods capable of providing flow controlled aerosol delivery of pharmaceutical formulations, which are actuated by breathing. According to one aspect of the invention, the invention aerosolizes the pharmaceutical formulation using the respiratory gas flow generated by the patient. According to certain embodiments of the present invention, the present invention can extract a powdered pharmaceutical formulation from a receptacle, grind the pharmaceutical formulation and deliver the pharmaceutical formulation to the lungs using a wide range of inhalation flow rates of the patient. According to another aspect of the invention, an apparatus and method are provided for effectively delivering a pharmaceutical aerosol deep into the lungs.

According to the invention, the flow of breathing gas is initially prevented from flowing to the lung until a predetermined vacuum is created by the user, and the flow of the breathing gas is suddenly started at the time when the predetermined vacuum is created. In certain embodiments, the pharmaceutical formulation is aerosolized using a rapid onset of breathing gas flow. According to this embodiment, when attempting to inhale through an open mouthpiece at one end of the device, initially, respiratory gas is prevented from flowing into the lungs. The breathing gas then flows abruptly into the lungs when a predetermined vacuum condition is generated by the user. The flow of breathing gas is used to extract the pharmaceutical formulation from the receptacle and place the pharmaceutical formulation within the breathing gas flow to form an aerosol.

At the time of inhalation, as the respiratory gas is initially prevented from flowing into the lungs, the devices and methods of the present invention provide a method of ensuring that the resulting gas flow has enough energy to extract the pharmaceutical formulation. In one aspect of the present invention, by arranging a valve in an air passage leading to the lungs and opening the valve to allow the breathing gas to flow, initially, the flow of the breathing gas is prevented from flowing into the lungs. According to the invention, the valve opens when the critical operating vacuum state caused by the suction attempt is exceeded. In this way, when the valve is opened, the resulting gas flow has sufficient energy to extract and aerosolize the pharmaceutical formulation.

According to another embodiment, the present invention provides an aerosolization device comprising a housing defining an air passage and a coupling mechanism for connecting a receptacle containing a pharmaceutical formulation to the air passage. The present invention also includes a valve that prevents breathing gas from flowing through the air passage until the critical operating vacuum is exceeded. At times above the critical operating vacuum, the valve opens to allow breathing gas to flow through the air passage and extract the pharmaceutical formulation from the receptacle to form an aerosol.

Various threshold valves may be used to prevent gas from flowing through the air passages, which will be described in detail below. For example, the valve includes a closure member having an opening and a through member passing through the opening when a critical operating vacuum condition is created. In particular embodiments, the closure member may comprise a thin film that flexes elastically and the through member may comprise a ball passing through the thin film when a critical vacuum is achieved. According to another aspect of the invention, the critical operating vacuum of the valve ranges from about 20 cm H ₂ 0 to 60 cm H ₂ O. According to certain aspects of the present invention, the valve is configured to be disposed within the receptacle. In this way, the valve can be easily manufactured with the receptacle.

According to another aspect of the present invention, the present invention provides an apparatus and method for regulating the flow of breathing gas to provide a consistent air flow regardless of the breathing rate of the user. In another aspect, the system includes a regulating system capable of regulating the flow of breathing gas through the air passage after the valve is opened. The combination of the critical valve and flow control according to the present invention can provide an aerosol delivery device and method effective for delivering aerosolized pharmaceutical formulations deep into the lungs.

 In another aspect, the devices and methods of the present invention may limit the flow of respiratory gas to less than a predetermined flow rate for a predetermined time. For example, the flow rate may be limited to a flow rate of less than about 15 liters per minute for a time of about 0.5 seconds to 5 seconds, which corresponds to a volume of 125 ml to 1.25 L. As described generally in PCT Application No. PCT / US99 / 04654, filed March 3, 1999, which was previously published for reference, and in co-pending US patent application Ser. No. 09 / 414,384, the regulation of flow rate is deeply closed. It is advantageous in terms of increasing the system bioavailability of the active agent of a given pharmaceutical formulation through absorption in.

Various techniques can be used to limit and regulate the flow of respiratory gases. For example, feedback may be provided to the user when an excessive flow rate occurs to allow the user to adjust his breathing rate. Examples of this provideable feedback include audio feedback including whistle, visual feedback such as indicators or level meters, and tactile feedback such as vibration. As another alternative, the flow of respiratory gas can be controlled by adjusting the size of the air passage leading to the lungs. For example, an elastically curved valve is used to provide flow resistance in accordance with the flow rate through the device to limit the flow to a predetermined flow rate.

According to one aspect of the present invention, the device of the present invention comprises a regulating system for restricting the flow of breathing gas through the air passage to a predetermined flow rate. For example, the conditioning system may be configured to limit the flow to a flow rate of about 15 liters or less per minute, for a predetermined time or for a given suction volume. Various flow regulators may be used to regulate the gas flow at a given flow rate, which will be described in more detail below. For example, the flow regulator may include a valve composed of an elastic element, such as a soft elastomer, which restricts the flow to a predetermined flow rate while also preventing flow in the opposite direction. Such a valve may have an orifice that allows air to flow through the valve in response to an applied vacuum and one or more soft walls surrounding the orifice. In this way, the walls are pulled towards each other by increased vacuum pressure levels, thereby reducing or closing the orifice area, providing greater or complete resistance to the flow. For example, such valves can be arranged in parallel flow paths. Once the flow rate becomes too high, the valve closes so all air passing through the device must pass through another path. By providing such a flow path with a predetermined size, the flow of gas through the device can be maintained below a critical flow rate.

According to certain aspects of the invention, the conditioning system may include a feedback system that provides information about the flow rate of the breathing gas. For example, the feedback mechanism may include a whistle that communicates with the air passage and generates whistles when the maximum flow rate is exceeded. Alternatively, it may include a restricting mechanism for limiting the size of the air passage. Conveniently, this restriction mechanism is adjustable to vary the flow rate of the breathing gas through the air passage. The limiting mechanism can be adjusted manually or automatically, such as by using an elastically curved material.

Optionally, an electronically controlled closed loop control system may be provided to adjust the limiting mechanism. According to one aspect of the present invention, the control system may be configured to restrict the flow at a predetermined flow rate for a predetermined time or for a predetermined volume, and then detect and regulate the restricting mechanism to allow for increased flow of respiratory gas through the air passage. Can be. In this way, the flow rate of the respiratory gas can be adjusted to limit the flow to the desired flow rate for a predetermined time to facilitate delivery of the pharmaceutical formulation to the lung. The control system can then be used to adjust the restriction mechanism to allow the user to conveniently fill his lungs with respiratory gas to deliver the pharmaceutical formulation deep into the lungs. Using the control system and control system according to the present invention, the device can be used by a large number of users with different inhalation flow rates and the device regulates the flow of respiratory gas so that the pharmaceutical formulation is properly delivered to the lungs. It is useful.

According to another aspect of the present invention, after limiting the flow rate for a desired time or during the intake volume, the size of the air passage can be increased to provide an increased flow rate. This can be achieved, for example, by opening other air passages through the device. In this way, the user can conveniently inhale without substantial resistance to fill the user's lungs with breathing gas and deliver the pharmaceutical formulation deep into the lungs.

According to an alternative aspect of the present invention, the present invention optionally allows for increased flow rate through the suction device after a predetermined time using various flow integrators to allow the user to conveniently open their lungs later in the process. Make it full. Such a flow integrator may include one or more movable members that move based on the volume of flow through the device. In this way, if the initial (adjusted) volume is inhaled, the member moves sufficiently to open other gas channels to allow for increased gas flow. Examples of usable flow integrators that include a movable piston, a clutch mechanism, a bellows filled with gas having a bleed hole, and the like will be described in more detail below.

Pharmaceutical formulations for use in the systems and methods of the present invention may be liquid or powder. According to one aspect of the invention, the pharmaceutical formulation consists of a powdered medicament. The flow of breathing gas is used to break up the powder once extracted from the receptacle. Optionally, various structures can be placed in the air passage to assist in the grinding process.

According to yet another embodiment, the present invention is provided with a receptacle consisting of a receptacle body that forms a cavity that is sealed by a pierceable access lead.

The receptacle also includes a threshold valve connected to its body. According to one aspect of the invention, the critical valve is configured to open upon receiving a vacuum of at least about 40 cm H ₂ O.

According to another aspect of the present invention, the present invention can use various techniques to ensure that the user properly positions the mouth over the mouthpiece during use of the aerosolization device. For example, a mouthpiece may be provided with the mouthpiece to allow the user to place his lips on the lip guard. As another example, the mouthpiece may comprise engagement means or other markings. Alternatively, one or more holes may be provided on the side of the mouthpiece. This hole must be covered by the lips to generate sufficient vacuum to operate the device. As another example, the mouthpiece may be circular to elliptical in shape. The oval portion should be able to be covered by the patient's mouth to generate sufficient vacuum to operate the device.

These and other aspects of the invention will be readily apparent to those skilled in the art from the following figures and detailed description of the invention.

1 is a graph depicting the average inhalation flow rate of 17 people, measured twice a week for 4 weeks.

2 is a graph showing the regulation of inhalation flow rate versus time in a patient according to the invention.

3 is a graph showing the regulation of inhalation flow rate versus time in another patient according to the present invention.

4 is a schematic diagram illustrating a system according to the present invention for extracting and grinding a pharmaceutical formulation from a receptacle and placing the pharmaceutical formulation in a flow of respiratory gas to form an aerosol.

5 is a perspective view of the aerosolization apparatus according to the present invention.

6 is a partial cutaway view of the aerosolization apparatus of FIG. 5 in an open or loading position.

7 shows the aerosolization apparatus of FIG. 6 in a closed or operating position in accordance with the present invention.

8 shows the aerosolization apparatus of FIG. 6 when inserting a receptacle according to the invention.

FIG. 9 shows the aerosolization device of FIG. 8 when the receptacle is inserted and the breathing gas flows through the aerosolization device after the aerosolization device is moved to a closed or operating position.

10 is a partial cutaway perspective view of a converging nozzle and receptacle capable of extracting a pharmaceutical formulation in accordance with the present invention.

FIG. 11 shows the receptacle and nozzle of FIG. 10, wherein the nozzle is moved further away from the bottom end of the receptacle to increase the flow rate of breathing gas through the nozzle according to the invention.

12 is a schematic cross-sectional view of an aerosolization system with a spring for regulating the flow of breathing gas through an aerosolization system according to the present invention.

13 is a schematic cross-sectional view of an aerosolization system with a flow control system for regulating the flow of respiratory gas through an aerosolization system according to the present invention.

14 illustrates one embodiment of a nozzle that may be employed to grind pharmaceutical formulations in accordance with the present invention.

15 is a perspective view showing one embodiment of an aerosolization apparatus according to the present invention.

16 is a perspective view showing another embodiment of the aerosolization apparatus according to the present invention.

FIG. 16A shows a cover of the aerosolization apparatus of FIG. 16. FIG.

17 is a perspective view of another embodiment of an aerosolization apparatus in accordance with the present invention showing the use of a flow rate feedback device.

18 shows another embodiment of an aerosolization apparatus according to the invention.

19 shows one particular embodiment of an aerosolization apparatus according to the invention.

FIG. 19A shows a disk with multiple receptacles inserted into the aerosolization apparatus of FIG. 19. FIG.

FIG. 19B shows the front end of the aerosolization apparatus of FIG. 19. FIG.

20 shows another embodiment of an aerosolization apparatus according to the invention.                 

20A is a view of the aerosolization apparatus of FIG. 20 showing the lid moved to the open position.

21 is a perspective view of another embodiment of an aerosolization apparatus according to the present invention.

22 is an illustration of one particular embodiment of an aerosolization device according to the present invention capable of retaining multiple drug bags.

FIG. 22A shows a clip used in the aerosolization apparatus of FIG. 22. FIG.

Figure 23 shows another alternative embodiment of the aerosolization apparatus according to the present invention.

FIG. 23A shows a mouthpiece cover of the aerosolization device of FIG. 23. FIG.

FIG. 24 illustrates a receptacle strip that may be used in the aerosolization apparatus of FIG. 23. FIG.

25 shows yet another alternative embodiment of an aerosolization apparatus according to the invention.

Figure 26 illustrates an embodiment of an aerosolization apparatus according to the present invention.

27 is a schematic diagram of a threshold valve according to the present invention.

Figure 28 illustrates a ball and thin film threshold valve in accordance with the present invention.

29 shows an umbrella shaped threshold valve in accordance with the present invention.

30 is a schematic diagram illustrating one embodiment of a threshold valve according to the present invention.

31A and 31B illustrate fin-shaped threshold valves in accordance with the present invention.                 

FIG. 32 shows a spindle valve in the form of a spindle in accordance with the present invention. FIG.

Figure 33 illustrates another spindle-type threshold valve in accordance with the present invention.

34A and 34B illustrate umbrella shaped threshold valves in accordance with the present invention.

Figure 35 illustrates a threshold valve in the form of a ball and magnet in accordance with the present invention.

36A and 36B illustrate a critical valve in the form of a bistable dome in accordance with the present invention.

37A and 37B illustrate a threshold valve in the form of a mechanical pressure switch in accordance with the present invention.

38 illustrates a critical valve in the form of a breakable thin film according to the present invention.

Figure 39 illustrates a threshold valve in the form of another mechanical pressure switch in accordance with the present invention.

40 shows a through valve critical valve in accordance with the present invention.

41 is a schematic diagram of a flow regulator according to the present invention.

42A and 42B illustrate a shuttle type flow regulator in accordance with the present invention.

Figure 43 illustrates a ball regulator flow regulator in accordance with the present invention.

44A and 44B illustrate a bellows-shaped flow regulator in accordance with the present invention.

45 shows a cone shaped flow regulator in accordance with the present invention.

46 shows another embodiment of a flow regulator according to the present invention.

Figure 47 illustrates a foam regulator in accordance with the present invention.                 

48 shows an umbrella-type flow regulator in accordance with the present invention.

49 illustrates a liquid reservoir flow regulator in accordance with the present invention.

50 shows another embodiment of a flow regulator according to the invention.

51 shows a flow regulator in the form of a spindle according to the invention.

Figure 52 illustrates a flow regulator in the form of an inflatable cone in accordance with the present invention.

53A and 53B illustrate an iris shaped flow regulator in accordance with the present invention.

FIG. 54 illustrates a paddlewheel type flow regulator in accordance with the present invention. FIG.

55A and 55B illustrate a flap shaped flow regulator in accordance with the present invention.

56A and 56B illustrate flow regulators in the form of elastomer duck bills in accordance with the present invention.

57-59 illustrate flow regulators in the form of alternative elastomer duckbills in accordance with the present invention.

60 is a schematic diagram illustrating a flow integrator of the penetrating form according to the present invention.

Fig. 61 is a schematic diagram showing a flow integrator in the form of diesel fuel according to the present invention.

62A and 62B illustrate a flow integrator in the form of a through shuttle in accordance with the present invention.

FIG. 63 shows a flow integrator in the form of an impeller in accordance with the present invention. FIG.

64 shows the end of the cam of the flow integrator of FIG. 63;

FIG. 65 shows a paddle wheel that may be used in the flow integrator of FIG. 63. FIG.

66A and 66B illustrate a shuttle integrator flow integrator in accordance with the present invention.

Figure 67 illustrates a brake timer flow integrator in accordance with the present invention.

FIG. 68 is a schematic diagram showing a brake and a wheel of the flow integrator of FIG. 67; FIG.

69 is a schematic diagram illustrating an aerosolization system according to the present invention with several components arranged sequentially.

FIG. 70 is a schematic representation of an aerosolization system with parallel diesel oil type flow integrators in accordance with the present invention. FIG.

71 is a schematic representation of an aerosolization system with a flow through integrator in parallel form according to the present invention.

72 is a front perspective view of one embodiment of an aerosolization apparatus according to the present invention.

FIG. 73 shows the device of FIG. 72 in a loading position; FIG.

FIG. 74 is a rear perspective view of the device of FIG. 72; FIG.

75 is a cross sectional view of the device of FIG. 73;

FIG. 76 is a cross sectional view of the device of FIG. 72; FIG.

FIG. 77 is a side view showing a cross section of the device of FIG. 72; FIG.

FIG. 78 shows the apparatus of FIG. 72 in a loading position; FIG.

79 is a front perspective view of another embodiment of an aerosolization apparatus according to the present invention.                 

FIG. 80 shows the apparatus of FIG. 79 in a loading position.

81 is a cross sectional view of the device of FIG. 79;

FIG. 82 shows the device of FIG. 81 when another flow path is opened to increase the flow of air through the device. FIG.

FIG. 83 is a side view of the device of FIG. 81; FIG.

84 is a front perspective view of another embodiment of an aerosolization apparatus according to the present invention.

FIG. 85 shows the apparatus of FIG. 84 when in the loading position; FIG.

86 is a cross sectional view of the device of FIG. 84;

87 is a side view of the apparatus of FIG. 86;

88 is a front perspective view of an embodiment of a mouthpiece in accordance with the present invention.

89 is a side view of an alternative mouthpiece in accordance with the present invention.

As used herein, “active agent” includes agents, agents, compounds, composites, or mixtures thereof, which often provides some beneficial benefit. This includes food, food supplements, nutrients, drugs, vaccines, vitamins and other beneficial agents. As used herein, the term includes any substance which produces a local or systemic effect in a patient and which acts physiologically or pharmacologically. Active agents that can be delivered include antibiotics, antivirals, antiepileptics, analgesics, anti-inflammatory and bronchodilators, and viruses, including inorganic and organic compounds, peripheral nerves, adrenergic receptors, anticholinergic receptors, skeletal muscle, cardiovascular system, smooth muscle, blood flow It may be a drug that acts on the circulatory system, synaptic site, nerve effector junction, endocrine system and hormone system, immune system, reproductive system, skeletal system, local hormone system, digestive system and embryo design, histamine system and central nervous system. Suitable agents include, for example, polysaccharides, steroids, sleeping and sedatives, psychostimulants, nerve stabilizers, anticonvulsants, muscle relaxants, anti-Parkinson's agents, analgesics, anti-inflammatory agents, muscle contractors, antimicrobials, hormones, as well as contraceptives, sympathetic stimulants, polypeptides. , Proteins (which may induce physiological effects), diuretics, support modulators, testosterones, antiparasitic agents, neoplastics, antitumor agents, hypoglycemic agents, nutritional and nutritional agents, growth agents, lipids, anti-inflammatory agents , Electrolytes, vaccines and diagnostics.

Examples of active agents useful in the present invention include insulin, calcitonin, erythropotin (EPO), factor VII, factor VII, ceredase, cerezyme, cyclosporin, granulocyte colony stimulating factor (GCSF), Alpha-1 protease inhibitors, elcatonin, granulocyte macrophage colony stimulating factor (GMCSF), growth hormone, human growth hormone (HGH), growth hormone secretion hormone (GHRH), heparin, low molecular weight heparin ( LMWH), interferon alpha, interferon beta, interferon gamma, interleukin-2, luteinizing hormone secreting hormone (LHRH), octostatin, somatostatin analogs including somatostatin analogs, vasopressin analogues, follicle stimulating hormone (FSH), insulin-like growth Factor, insulintropin, interleukin-1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, macrophage colony stimulating factor (M-CSF), nerve growth factor, parathyroid hormone (PTH), thymosin eggs PAR 1, IIb / IIIa inhibitors, alpha-1 antitrypsin, respiratory syncytial virus antibodies, cystic fibrosis transmembrane regulatory (CFRT) genes, deoxyribonucleases (Dnase), bactericidal / permeability enhancing proteins (BPIs), Anti-CMV antibody, interleukin-1 receptor, 13-cis retinoic acid, pentamidine isethionate, albuterol sulfate, metaproterenol sulfate, beclomethasone dipropionate, triamcinolone acetamide , But not limited to, budnonide acetonide, ipratropuim bromide, flunisolide, fluticasone, chromoline sodium, tartarate ergotamine and the like, and antagonists and agonists described above It doesn't work. In addition, the active agent may be a nucleic acid present as a naked nucleic acid molecule, a spiral vector associated with a spiral particle, a nucleic acid associated with or coalesced with a lipid or lipid-containing substance, a plasmid DNA, RNA, in a form suitable for the transformation or metastasis of cells in the alveolar region of the lung, Other nucleic acid constructs. The active agent can be in various forms such as soluble and non-soluble charged or uncharged molecules, molecular complexes, or components of salts soluble in the drug. The active agent may be a naturally occurring molecule, or may be recombinantly formed or analogous to a naturally occurring or recombinantly formed active agent with one or more nucleic acids added or deleted. In addition, active agents may include dead or attenuated live viruses suitable for use as vaccines.

Since the powders of the invention are generally complex (ie composed of a wide range of particle sizes), the "mass median diameter" or MMD refers to the size of the average particle measured. Any of the various techniques commonly used to determine average particle size may be used, but the MMD values reported herein are determined by centrifugal precipitation.                 

The "mass medium aerodynamic diameter" or MMAD is a measure of the aerodynamic size of the dispersed particles. This aerodynamic diameter is used to describe aerosolized powders in terms of sedimentation behavior and is generally the diameter of spheres of unit density with the same sedimentation rate as particles in the air. Aerodynamic diameter is meant to encompass particle shape, density and physical size of the particle. As used herein, MMAD refers to the midpoint or median of the aerodynamic particle size distribution of the aerosolized powder determined by continuous impact.

The present invention provides methods and systems for administering aerosolized pharmaceutical formulations using respiratory gas flow generated by a patient. Aerosolizable pharmaceutical formulations include powdered pharmaceuticals, liquids or suspensions, and the like, and may also include active agents. The device of the invention can be used for one administration or for multiple administrations.

In some embodiments, the flow of respiratory gas generated by the patient is used to extract the pharmaceutical formulation from the receptacle, crush the pharmaceutical formulation, and deliver the pharmaceutical formulation to the patient's lungs. A particular advantage of the present invention is the ability to perform this function regardless of the patient's natural respiratory rate. Thus, according to one aspect of the invention, the inhaled respiratory gas is controlled to deliver the pharmaceutical formulation appropriately to the lungs within an acceptable flow rate range.

According to another aspect of the present invention, the present invention is configured such that the flow rate of the injection gas is adjusted so that the gas has sufficient energy to extract the pharmaceutical formulation from the receptacle, grind and deliver it to the lungs. In some cases, the present invention is initially configured to maintain a suction flow rate of less than or equal to a maximum, for a predetermined time or for a predetermined suction volume, upon delivery of the medication. In this way, the aerosolized formulation will flow at an acceptable flow rate to improve the ability to cross the patient's air passages into the lungs. After the initial delivery of the pharmaceutical formulation to the lung, some embodiments of the invention are configured to breathe at the usual respiratory flow rate to fill the patient's lungs with respiratory gas and also deliver the pharmaceutical formulation to the lung.

In order to aerosolize the pharmaceutical formulation, the flow of respiratory gas preferably has sufficient energy to extract the pharmaceutical formulation from the receptacle. To ensure that the breathing gas has sufficient energy, the present invention can be configured to prevent the breathing gas from flowing into the patient's lungs when the patient is about to breathe. Then, suddenly, after reaching the critical vacuum state, the breathing gas can be allowed to flow into the lungs of the patient. By suddenly allowing the flow of breathing gas when a sufficient vacuum is applied by the user, a relatively high flow rate is achieved to supply sufficient energy to the gas flow. One way to accomplish this process is to place a restrictor valve or another obstruction mechanism in the patient's air passage that prevents respiratory gas from entering the patient's lungs when the patient is about to breathe. The restriction valve is then quickly removed or opened to allow breathing gas to flow into the lungs. Thus, the patient may be instructed to breathe until the critical operating vacuum is overcome. The initial working vacuum can be configured to generate sufficient energy for the resulting gas flow when gas is allowed to flow into the patient's lungs. Preferably, the critical vacuum is in the range of 20 cm H ₂ O to 60 cm H ₂ O so that the resulting gas stream has sufficient energy to extract and grind the pharmaceutical formulation. Most preferably, the critical vacuum is at least 40 cm H ₂ O.

Various threshold valves may be used to prevent the breathing gas from reaching the patient's lungs until a critical breathing vacuum is achieved. For example, the threshold valve can be configured to bend when the critical vacuum is satisfied or exceeded, including an elastically curved valve such as a flexible member disposed across the air passage. Alternatively, the threshold valve may include a score member configured to rupture or break once the threshold pressure is met or exceeded. As another example, the threshold valve can include an elastomeric member having an opening. The ball passes through the opening once the critical pressure is achieved or exceeded. Other types of critical valves include bistable mechanisms, diaphragms, and the like.

According to a particular aspect of the present invention, the critical valve may be incorporated into a receptacle containing a pharmaceutical formulation. In this way, in each case where a new receptacle is inserted into the aerosolization device, the device is provided with a new threshold valve. This is particularly advantageous if the threshold valve comprises a member configured to rupture or break after the threshold vacuum is satisfied or exceeded.

Once the breathing gas is allowed to flow into the lungs, the flow rate of the breathing gas (in some cases) needs to be controlled or adjusted so that the gas does not exceed the maximum flow rate during delivery of the pharmaceutical formulation to the lungs. In general, the flow rate of the respiratory gas is adjusted to about 15 liters or less per minute, corresponding to an inhalation volume of about 125 mL to 1.25 L for a time of 0.5 to 5 seconds so that the aerosolized formulation passes through the patient's air passages into the lungs. Allow inflow. For example, as described above in connection with FIG. 1, some patients have an inhalation rate above the desired maximum flow rate.

For those who breathe innately above the maximum required flow rate, the present invention slows down the flow rate for the time that the aerosolized formulation is delivered to the lungs. This is illustrated in the graphic of FIG. At time T ₁ , the patient is inhaling breathing gas to flow into the patient's lungs. At time T ₁ , the flow rate is well above the preferred starting flow rate (Q _start ) for initially extracting the pharmaceutical formulation from the receptacle as described above. Thus, this breathing person does not need a critical valve or other flow prevention mechanism. In the time T ₂ immediately after the time T ₁ is adjusted such that the flow rate is the flow rate Q _passing below. The flow rate is maintained below the Q _delivery flow rate from time T ₂ to time T ₃ , at which time the aerosolized formulation is delivered to the patient's lungs. After time T ₃ , the regulation of the gas flow is stopped and the patient is able to inhale at regular flow rates, filling the lungs with respiratory gas, which serves to further deliver the pharmaceutical formulation deep into the lungs.

3 graphically illustrates an example of a patient whose inherent suction flow rate is below Q _delivery . As shown in FIG. 3, by preventing the flow of respiratory gas during inhalation of the patient and then suddenly allowing the flow of respiratory gas, the starting flow rate at time T ₁ becomes Q _transfer . In this method, sufficient energy is provided to extract the pharmaceutical formulation from the receptacle. As the patient continues to inhale, the flow rate drops sharply below the Q _delivery flow rate because the patient's inherent suction flow rate is less than the Q _delivery flow rate. Therefore, after the time T ₁ , it is not necessary to adjust the inhalation flow rate of the patient, thereby allowing the patient to inhale at a comfortable level.

Various configurations and techniques can be provided to adjust the suction flow rate below the Q _transfer flow rate from time T ₂ to time T ₃ . As one example, various forms of feedback can be provided to the patient to enable the patient to self-adjust the inhalation flow rate. For example, the aerosolization device may be provided with a whistle which generates a whistle sound when the flow rate of the patient exceeds the Q _delivery flow rate. Other types of feedback available include visual feedback, tactile feedback, auditory feedback, and the like. Optionally, the controller may be provided with a timing mechanism that can indicate to the user when time T ₃ has elapsed so that the user can end a comfortable level of inhalation.

As another example, the inhalation flow rate of the patient may be adjusted by limiting or retarding the gas being inhaled. For example, the flow volume of the intake gas may be controlled by changing the size of the air passage. The adjustment method can be manual, semi-automatic or automatic. For example, the user can control the flow rate by adjusting the size of the air passage by hand or by restricting the air passage. Alternatively, the size of the air passage may be adjusted based on the patient's own intake, which is described in more detail below. In another example, an automatic system with one or more flow sensors may be provided to adjust the size of the air passages to control the flow of breathing gas.

One particular advantage of controlling the intake flow rate by limiting the flow of breathing gas is that relatively high pressure drops can occur. Since power is generally proportional to both pressure drop and flow rate, the flow rate can be kept low while providing enough energy to aerosolize the formulation to deliver the formulation to the patient's lungs.

Alternatively, the flow of respiratory gas may be controlled by placing an orifice or other restrictive member in the patient's air passageway adapted for use with a particular patient. In this method, the aerosolization device can be adapted to a particular patient by simply using an orifice sized according to the patient's inhalation flow rate.

The device according to the invention may have a continuous or parallel flow path. In either case, it is desirable to maintain a constant and predetermined flow rate for many patient populations. As shown in Fig. 4, in the case of the continuous configuration, it is preferable that the flow resistance and the vacuum relation are almost linear. For example, as shown in FIG. 70, in the case of the parallel configuration, it is preferable that the flow resistance and the vacuum relationship are very nonlinear.

Referring now to FIG. 4, a system 10 using a continuous configuration of extracting powdered medicine from the receptacle 12 using the breathing gas of an inhaled patient will be described. The system 10 has a threshold valve 14, which has a vacuum in its downstream line 16 with a vacuum of 20 to 60 cm H ₂ O, preferably 40 cm H ₂ O. Is configured to open when Also connected to the line 16 is a conditioning system 18 which regulates the flow of breathing gas through the system 10. As an example, the regulation system 18 may include a restriction mechanism that may be used to control the internal size of the line 16 and thus regulate the flow of breathing gas through the line 16. The adjustment system 18 may be convenient to include a control system for adjusting the restriction mechanism. The control system can be operated by hand or in an automatic manner using a controller. For example, a gas flow sensor may be placed in the system 10 and connected to a controller to measure the flow rate of respiratory gas through the system. Using this information, a controller can be used to control the degree of limitation of line 16. Although the regulating system 18 is shown upstream of the receptacle 12, it will be appreciated that this regulating system 18 may be provided at other locations, including downstream of the receptacle 12 and upstream of the threshold valve 14. .

The regulation system 18 is connected to the receptacle 12 by line 20. A line 22 in communication with the grinding mechanism 24 is connected to the outlet side of the receptacle 12. In this method, the powder extracted from the receptacle 12 is ground and advanced into the patient's lungs before leaving the system 10. At the exit side of the grinding mechanism 24 there is a line 26 which is connected to a mouthpiece (not shown) which the patient inhales. Thus, the system 10 allows the patient to accept the aerosolized dose of medicine by inhaling from the mouthpiece until the patient has generated sufficient vacuum to open the critical valve 14. When the critical valve 14 is open, the powdered medicine is extracted from the receptacle 12 and passes through the grinding mechanism 24. At the same time, the conditioning system 18 controls the flow of respiratory gas within the tolerance to allow the aerosolized medicament to properly enter the patient's lungs. After a period of time, the conditioning system 18 is configured to shut down so that the patient inhales to a comfortable level, fills the lungs with respiratory gas and moves the delivered medication deep into the lungs.

Referring now to FIG. 5, a preferred embodiment of the aerosolization apparatus 28 will be described. The aerosolization device 28 comprises a substantially cylindrical housing 30 with a mouthpiece 32 at one end. The housing 30 further comprises openings 34, 36 and 38 which form a flow path for the breathing gas, which is described in more detail below. Conveniently, a partition 40 is provided between the openings 36, 38 to allow the flow of breathing gas to temporarily pass the outside of the housing 30. Similarly, a partition 42 is provided so that breathing gas can be easily introduced into the housing 30 through the opening 34 (see FIG. 6).

The receptacle carrier 44 is pivotally connected to the housing 30. Conveniently, a pin 46 is used to pivotally connect the receptacle carrier 44 to the housing 30. The receptacle carrier 44 may be moved to a closed or actuated position as shown in FIG. 7. As best shown in FIGS. 6 and 7, the receptacle carrier 44 has an opening 48 that is aligned with the opening 34 when the receptacle carrier 44 is moved to the closed position. The receptacle carrier 44 further has another opening 50 disposed below the two perforated tabs 52 on the housing 30.

As best shown in FIG. 8, once the receptacle carrier 44 is moved to the open position, the receptacle 54 can be inserted into the aerosolization apparatus 28. Receptacle 54 includes a receptacle body 56 having a chamber 58 (shown in dashed lines) for holding powdered medicine. The receptacle body 56 is configured such that the upper portion of the chamber 58 may be perforated by the tabs 52, as described in more detail below. The receptacle body 56 is disposed with a critical valve 60 having a thin film configured to rupture or break at a particular critical vacuum.

The receptacle 54 is inserted into the aerosolization device 28 such that the threshold valve 60 is aligned with the opening 36. In addition, chamber 58 lies within opening 50. Once the receptacle 54 is inserted into the receptacle carrier 44, the receptacle carrier 44 is moved to the closed or actuated position as shown in FIG. In the closed position the threshold valve 60 is aligned with the opening 34. In addition, the tab 52 punctures the body 56 above the chamber 58 and peels the lid to provide a pair of openings that allow access to the powder contained within the chamber 58. Once the receptacle carrier 44 is moved to the closed position, the user can try to inhale by placing his mouth over the mouthpiece 32. The flow of breathing gas through the aerosolization device 28 is prevented until the user creates a vacuum sufficient to open the critical valve 60. At this point, as shown by the arrows, the breathing gas violently flows through the opening 34, through the opening 36, through the chamber 58, through the opening 38 and out of the mouthpiece 32. It can flow.                 

Referring now to FIG. 10, an example of a technique that can be used to regulate the flow of breathing gas through an aerosolization device, such as an aerosolization device 28, will be described. 10, a receptacle 62 having a chamber 64 filled with a pharmaceutical formulation (not shown) is shown. In FIG. 10, the puncture tube 66 has already perforated the lid above the chamber 64, and the distal end 68 of the tube 66 is disposed in the chamber 64. In FIG. 10, the distal end 68 of the tube 66 is disposed near the bottom of the chamber 64. In this method, the size of the air passage between the distal end 68 and the bottom of the chamber 64 is reduced to limit the breathing gas flowing inside the chamber 64 and out of the perforated tube. As shown in FIG. 11, the distal end 68 is moved vertically upward and further away from the bottom end of the chamber 64. In this way, the flow rate of the breathing gas may be increased.

Various techniques may be used to adjust the distance between the distal end 68 and the bottom of the chamber 64. For example, one technique employs the use of suction force generated by the inhalation of a patient. More specifically, as the patient begins to inhale, the vacuum source created in the tube 68 by inhalation tends to move the bottom end of the chamber 64 toward the distal end 68. Various mechanisms may be used to control the distance between the distal end 68 and the bottom end of the chamber 64. For example, various deflection mechanisms may be included that control the relative movement between the receptacle 62 and the puncture tube 66. Automatic mechanisms such as solenoids, pistons and the like may also be used. Moreover, various manual techniques may also be used, including the use of a user's hand or finger.                 

One of the features of the perforated tube 66 is that it forms a converging nozzle that acts as a grinder for the powder contained within the chamber 66. More specifically, as the patient inhales and extracts the powder from the chamber 64, the converging flow path generated by the perforated tube 66 pulverizes the powder to facilitate aerosolization of the powder and placement in the lungs. There is a tendency.

Referring now to FIG. 12, one technique for controlling the flow of breathing gas through the aerosolization device will be described by describing one embodiment of the aerosolization device 70. For ease of explanation, since only a portion of the aerosolization apparatus 70 is shown, it should be understood that other components may be used to complete the aerosolization apparatus. The aerosolization device 70 includes a housing 72 and a receptacle carrier 74. Receptacle carrier 74 may be configured to be movable relative to housing 72 for convenient loading and unloading of receptacle 76. Receptacle 76 includes a chamber 78 and a threshold valve 80 that may be configured similarly to other embodiments described herein. The receptacle carrier 74 includes an opening 82 that is aligned with the valve 80 to allow breathing gas to flow through the valve 80 once opened. The housing 72 is connected with a perforated tube 84 that perforates the receptacle 76 to allow access to the chamber 78 in a manner similar to that described in the previous embodiment. In this manner, if the patient inhales from the aerosolization device 70, the threshold valve 80 opens when the critical vacuum is overcome. Thereafter, the breathing gas flows through the chamber 78 and flows out of the puncture tube 84 as shown by the arrow.                 

The aerosolization apparatus 70 further includes a spring 86 disposed between the housing 72 and the receptacle carrier 74. Once the valve 80 is open, the vacuum in the puncture tube 84 causes the bottom end of the chamber 78 to enter the puncture tube 84. The spring constant of the spring 86 may be selected to control the gas flow through the aerosolization device by controlling the distance between the bottom end of the chamber 78 and the perforation tube 84. In some cases, it may be desirable to select the spring constant of the spring 86 based on the average suction flow rate generated by the patient. In this way, the aerosolization device 70 can be adapted to the particular patient. The aerosolization apparatus 70 further includes a fin 88 for maintaining a gap between the bottom of the chamber 78 and the perforation tube 84 at a predetermined distance. In this way, the chamber 78 is not fully retracted with respect to the perforated tube 84.

Referring now to FIG. 13, an aerosolization apparatus 90 will be described. The aerosolization apparatus 90 may be composed of elements similar to those described above in connection with the aerosolization apparatus 70. Thus, for ease of explanation, similar elements used in the aerosolization apparatus 90 are indicated by the same reference numerals used to describe the aerosolization apparatus 70 and are not described further. The aerosolization apparatus 90 differs from the aerosolization apparatus 70 in that it uses an electronic controller 92 to control the distance between the puncture tube 84 and the bottom end of the chamber 78. Electronic controller 92 is electronically connected to solenoid 94 that can expand or contract to control the gap between perforated tube 84 and chamber 78. Optionally, the flow control sensor 96 can be placed anywhere within the air passage of the aerosolization device 90 to sense the flow rate through the aerosolization device. When the controller 92 receives a signal from the flow control sensor 96, it can send a signal to the solenoid 94 to adjust the gap and thereby adjust the flow rate. One of the advantages of using the controller 92 is that the solenoid 94 may include a timing circuit such that the solenoid 94 is fully inflated after a predetermined time. In this way, once the aerosolized formulation reaches the patient's lungs, the solenoid 94 can be fully inflated to allow the user to inhale comfortably and fill the lungs with respiratory gas without substantial resistance.

Referring now to FIG. 14, another embodiment of a nozzle 98 that may be disposed downstream of the receptacle will be described. The nozzle 98 has a tubular structure 100 having an outlet 102 and a constriction 104. Once the pharmaceutical formulation is extracted from the receptacle, it passes through the tubular structure 100 as shown by the arrows. The change in direction caused by the outlet 102 causes the ground powder to contact the walls of the tubular structure 100 to aid in the crushing of the pharmaceutical formulation. When the shrinkage 104 is reached, the powder is further agitated to increase the flow so that the powder can be further ground. While one outlet is shown followed by a shrinkage, it should be understood that various configurations of directional change and / or various configurations to facilitate pulverization of the powder may be provided in various tubular structures.

Referring now to FIGS. 15-26, embodiments of various aerosolization apparatuses will be described. Although not shown, the aerosolization apparatus of FIGS. 15 to 26 typically includes a perforated tube having one or more perforation structures capable of perforating leads of receptacles similar to the above embodiments. These devices may also include a threshold valve and a regulating system to regulate the flow of respiratory gas towards the lungs of the patient in a manner similar to that described in the foregoing embodiments. In addition, it should be understood that the components of the various devices of FIGS. 15-26 may be dispensed, replaced, and / or replaced with one another.

First, an embodiment of the aerosolization device 106 will be described with reference to FIG. 15. The aerosolization device 106 has a housing 108 with a lid 110. The lid 110 can be moved to an open position to receive the seat 112 of the receptacle 114. The lid 110 includes several buttons 116 that can be pressed prior to suction to puncture the accessory receptacle 114. The lid 110 is conveniently provided with a window 118 that can indicate the sheet 112 to be loaded and can also show the data and shape of the medication printed on the sheet 112. The housing 108 further includes a slidable cover 122 that can slide over the mouthpiece 120 when not in use with the mouthpiece 120.

When the patient is ready for treatment, the patient slides the cover 122 to expose the mouthpiece 120. The user then presses one of the buttons 116 and inhales mouth over the mouthpiece 120. Once all buttons 116 have been pressed, the seat 112 can be replaced with a new receptacle seat.

FIG. 16 shows an aerosolization device 124 having a cover 126 (see also FIG. 16A) and a drawer 128 slidable within the cover 126 as indicated by the arrow. Retractor 128 is configured to hold receptacle 130. As shown in FIG. 16A, when retractor 128 is closed, receptacle 130 remains in cover 126. Conveniently, the chamber of the receptacle 130 may be configured to puncture when the inlet 128 is closed. Several pressure buttons 132 may be provided to allow the injector 128 to be turned back for later use. The cover 126 further includes a window that can indicate the mouthpiece 134 and the receptacle 130 to be loaded and at the same time show the data and shape of the medication. Optionally, a counter 138 may be provided to show the cumulative number of uses of the aerosolization device.

FIG. 17 illustrates an aerosolization device 140 having a housing 142 having a mouthpiece 144 and a lid 146. The lead 146 is movable between the open position and the closed position as shown by the dashed-dotted line. Opening the lid 146 allows the receptacle 148 to be placed in the housing 142. Closing the lid 146 causes the receptacle 148 to be drilled so that the aerosolization device 140 is ready for operation. Conveniently, lid 146 may have a raised window 152 that includes balls 152. The rear region of the window 150 is arranged to communicate with the air flow path, thereby allowing the ball 152 to move within the region that depends on the flow rate of the breathing gas passing through the aerosolization device 140. Conveniently, plus and minus signs can be used to provide the patient with visual feedback about the flow rate through the aerosolization device. In this way, the patient can adjust the inhalation based on visual feedback. Optionally, the aerosolization device 140 may have a storage compartment 154 that holds an extra receptacle 148.

18 shows an aerosolization device 156 having a housing 158 having a mouthpiece 160 and a lid 162. The hinge 164 pivotally connects the lid 162 to the housing 158. The lid 162 is movable between the open position and the closed position. When in the open position, receptacle 166 may be loaded into housing 158. Then, the lid 162 is closed, in which the receptacle 166 is visible through the window 168. Lead 162 includes a pressure button 170 that presses and drills receptacle 166 prior to use.

FIG. 19 shows an aerosolization device 172 having a housing 174 and a door 176 connected to the housing 174 by a hinge 178. As shown in FIG. 19A, disk 180 having multiple receptacles 182 is insertable into aerosolization apparatus 172. Conveniently, each receptacle may be numbered as shown in FIG. 19A. The door 176 has a dial rotatable to rotate the disk 180 within the aerosolization device 172. The door 176 also has a window 186 for viewing the receptacle perforated by the rotary dial 184. When ready to receive treatment, the user begins to inhale by placing his mouth over the nose 187 of the aerosolization device 172. Inhalation of the patient opens lid 188 to allow the aerosolized formulation to enter the patient's lungs. To receive another treatment, the patient may simply prepare the operation of the aerosolization device 172 by simply turning the dial 184 to the next receptacle to be perforated.

Referring now to FIGS. 20 and 20A, an alternative aerosolization apparatus 190 will be described. The aerosolization device 190 has a housing 192 and a lid 194 connected to the housing 192 by a hinge 196. The aerosolization device 190 further includes a mouthpiece 198 that the patient inhales. As shown in FIG. 20A, the aerosolization apparatus 190 is in an open position with the receptacle 200 disposed in the loading position. The lid 194 can then be closed to the position shown in FIG. 20. The lid 194 includes a pressure button 202 that presses against the receptacle 200 to allow the pharmaceutical formulation to be extracted. The lead 194 also includes a timer 204 that is manually set by the user pulling the timer 204 toward the button 202 before actuation. The user then begins inhalation from the mouthpiece 198 to aerosolize the pharmaceutical formulation. The user preferably inhales until the timer 204 is activated. As shown in FIG. 20A, the lid 194 may include a number of storage locations for receiving additional receptacles 200.

FIG. 21 shows an aerosolization device 206 having a housing 208 with a slot 210 for receiving a receptacle 212. The aerosolization device 206 further includes a caulking device 214 that can be caulked to cause the receptacle 212 to be drilled. The aerosolization device 206 further includes a trap door 216 and an extendable mouthpiece 218 (shown in dashed line). When the caulking device 214 is caulked to puncture the receptacle 212, the trap door 216 is also opened to extend the mouthpiece 218.

Referring to FIG. 22, another aerosolization device 220 will be described. The aerosolization device 220 has a housing 222 and a clip 224 that can be connected to the housing 222. As best shown in FIG. 22A, the clip 224 includes a receiving area 226 and a waste area 228. The receiving area 226 includes a number of receptacles 230 that can be loaded into the housing 222 as described below. Once used, the receptacle is discharged to the waste zone 228. Conveniently, detachable seal 232 may be disposed in storage area 226. An advantage of using the clip 224 is that a replacement clip for freshly supplying the receptacle can be easily connected to the housing 222, allowing the aerosolization device 220 to be used multiple times.

As best shown in FIG. 22, housing device 220 further includes a rotatable dial 234 that is rotated to advance one of the receptacles 230 into housing 222 in storage area 226. . Once placed in the housing 222, the receptacle 230 is perforated. The housing 222 also includes a counter 236 that shows how many receptacles remain unperforated. The mouthpiece cover 238, which is bound in a string, is connected to the housing 222 and removed prior to suction.

Thus, to use the aerosolization device 220, the user simply advances the next receptacle by drilling the dial 234 to puncture. The user removes and inhales the cover 238 to aerosolize the pharmaceutical formulation and deposit the formulation into the lungs of the patient. When ready for the next dosing, the dial 234 is rotated again so that the used receptacle is ejected into the waste area 228 and the other receptacle is advanced. If all receptacles have been used, remove the clip 224 and insert the replacement clip.

FIG. 23 shows an aerosolization device 240 having a housing 242 and a lead 244 pivotally connected to the housing 242. A removable mouthpiece cover 246 is also provided (see also FIG. 23A). The cover 246 is removed before inhalation by the patient. The aerosolization device 240 is configured to hold a strip 248 (shown in FIG. 24) of the receptacle 250. Once the strip 248 is located within the housing 242, the slide 252 can be moved to indicate the receptacle that it wants to be perforated. The slide 252 can then be pressed to puncture the selected receptacle. Optionally, slide 252 may be connected to tubing in aerosolization apparatus 240 so that tubing may be moved with the slide 252 to a suitable receptacle. The aerosolization device 240 may also include a whistle 254 that generates an auditory signal when the user inhales above the maximum suction flow rate. The user may simply inhale at a slow flow rate until the whistle 254 generating the whistle stops.

FIG. 25 shows an aerosolization device 256 having a housing 258 and a mouthpiece cover 260 fastened to the housing 258. Cover 260 is removed before use. The housing 258 further includes a slot 262 extending through the housing 258. In this manner, strip 264 of continuous receptacle 266 may be supplied through slot 262. Alternatively, strip 264 may be divided into segments such that individual receptacles may be fed into slot 262. Housing 258 includes a button 268 that can be punched by pressing the loaded receptacle.

When the patient begins to inhale, the flow rate is monitored by the gas gauge 270. In this way, the user is provided with visual feedback that helps to inhale at a moderate flow rate. Optionally, the housing 258 may include a clip 272 that allows the aerosolization device 258 to be carried in a pocket, such as a pen.

FIG. 26 shows an aerosolization device 274 having a housing 276 with a mouthpiece 278 and a rotating body 280 rotatable with respect to the housing 276. The aerosolization device 274 is configured to receive the receptacle pack 282 at the rear end of the device 274. Receptacle pack 282 includes a number of receptacles 284 that can be perforated when ready for use. Although the shape of the receptacle pack 282 is shown as being cylindrical, it should be understood that other shapes, including square tubes, may be used.

When the receptacle pack 282 is inserted into the aerosolization device 274, the rotating body 280 rotates to advance one of the receptacles to the engaged position where the receptacle is perforated. Conveniently, housing 276 has a counter 286 showing the number of remaining receptacles. If the patient breathes at an excessive flow rate, the housing 276 vibrates to provide feedback to the user so that the patient can adjust the intake flow rate.

A wide range of critical valves can be used to prevent the flow of gas into the patient's lungs until the patient has created sufficient vacuum to extract the powder from the receptacle. Such a valve is configured to prevent the flow of any gas until the vacuum generated by the patient matches or exceeds the critical operating pressure of the valve. After the valve is opened, very little flow resistance is provided by the valve. If the flow stops, the valve can be configured to reset the previous start position.

Critical valve configured to open at a pressure of about 20 cm H ₂ O to about 60 cm H ₂ O, more preferably at least about 50 cm H ₂ O to allow gas flow through the aerosolization device in the direction indicated by the arrow. A schematic diagram of a valve system 300 with 302 is shown in FIG. 27. In this method, a relatively high flow rate is achieved for a short period of time at the start of inhalation, allowing the powder to diffuse out of the receptacle.

Optionally, the valve system 300 can include a check valve 304 that prevents flow to the user through the device. Such check valves may be incorporated in any location of the aerosolization apparatus and may be integrated with the threshold valves for convenience. Valve system 300 may be configured so that there is little resistance to gas flow once valve 302 is opened. In some cases, valve system 300 may be configured to have a reset characteristic to reset valve 302 if necessary. In some cases, the valve system 300 may be configured to have a regulating mechanism that can adjust the critical operating pressure to lower any vacuum level and / or raise the countercurrent resistance pressure.

One form of critical valve that can be used is a silicone rubber configured to initiate flow at the desired critical pressure and resist backflow. This valve also resets itself without the need for mechanical resistance means. Examples of such valves are described, for example, in U.S. Pat. Included as.

Examples of various types of critical valves that can be incorporated into an aerosolization apparatus are shown in FIGS. 28 to 40. 28 shows a through critical valve 306 consisting of a housing 308 having an inlet 310 and an outlet 312. A thin film 314, such as an elastomeric thin film, is disposed across the interior of the housing 308 and has a central opening 316. The ball 318 is sealed within the housing 308 and is configured to penetrate the opening 316 when sufficient vacuum has been created by the user as shown by the dotted line. Once the ball 318 passes through the membrane 314, gas flow through the housing 308 is allowed by passing through the passage 320. Conveniently, reset rod 322 may be used to press ball 318 back to the other side of membrane 314 to reset the valve for other uses.

29 illustrates an umbrella through valve 324. The valve 324 has a housing 326 having a support member 328 for supporting the umbrella member 330. The housing 326 also includes a tab 332 which prevents axial movement of the umbrella member 330 until the user creates a sufficient vacuum. When sufficient vacuum is generated, the umbrella member 330 is bent and passed through the tab 332 as shown by the dotted line. Next, gas is allowed to flow through the opening 334 of the support member 328. The reset rod 336 can be used to retract the tab 332 by pressing the umbrella member 330 before other uses.

30 shows a critical valve 338 having a tubular housing 340 disposed in the transverse direction such that the valve member 342 pivots. The biasing member 344 deflects the valve member 342 relative to the tab 346. In this way, gas is allowed to flow through the housing 340 once a sufficient vacuum is formed to overcome the biasing force so that the valve member 342 can be opened as shown by the dashed line.                 

31A shows a flapper valve 348 that can be used in the tubular housing. The flapper valve 348 has two valve members 350 pivotally connected to the shaft 352. A spring (not shown) biases valve member 350 to the position shown in FIG. 31A. If sufficient vacuum force is provided, the valve member 350 moves to the open position shown in FIG. 31B to overcome the spring force, allowing gas to flow.

FIG. 32 illustrates a spindle shaped valve 354 with a tubular housing 356 having a spindle 358 held between tabs 360, 36. The through channel 362 is arranged such that gas can flow through the channel 362 and around the spindle 358 when the vacuum generated by the user moves the spindle toward the tab 361. The frictional force between the spindle 358 and the housing 356 can vary depending on the desired threshold force required to open the valve.

33 shows another spindle shaped valve 364 with a tubular housing 366 having a stop 368. The spindle 370 is disposed in the housing 366 to be near the stop 368 to prevent the flow of gas through the housing 366. When sufficient vacuum is generated by the patient, the spindle 370 slides in the housing 366 away from the stop 368. In this way, gas can flow through the housing 366.

34A shows a threshold valve 372 having a tubular housing 374 with a support 376 having a ball 380 and holding an umbrella member 378 that can be flipped out. The ball 380 serves to fix the umbrella member 378 to the support 376 when a vacuum is applied by the user. As shown in FIG. 34B, the umbrella member 378 is configured to flip out when sufficient vacuum is generated by the user. When the umbrella member is in the inverted position, gas flows through the opening 382 of the support 376 as shown. Umbrella member 378 may be reset to the position shown in FIG. 34A prior to other use.

The critical valve may be a valve designed to be in the open and closed positions alternately based on the predetermined magnetic field strength. For example, FIG. 35 shows a critical valve 384 with a housing 386 that holds a steel ball 388. Within the housing 386 is also disposed an elastomeric gasket 392 having a magnet 390 and a central opening 394 smaller in diameter than the ball 388. In this method, the magnet 390 holds the ball 388 in the opening 394 to block the flow of gas through the housing 386. If the user provides sufficient vacuum, the ball 388 is moved to the stop 396, as shown by the dashed line. At this time, the gas flows freely around the ball 388 and through the opening 394. The magnetic field is configured to be strong enough so that when the user stops inhaling the ball is reset to block air flow.

36A shows a threshold valve 398 with a tubular housing 400 having a restriction 402 with a central orifice 404. The bistable dome 406 is disposed across the interior of the housing 400 to cover the orifice 404 when connected to the support 407 and in the position shown in FIG. 36A. Once the user provides sufficient vacuum, the dome 406 performs a bistable function to move to the position shown in FIG. 36B. In this manner, as shown by the arrow, gas may pass through the orifice 404 and then through the opening 408 of the support 407.

FIG. 37A shows a threshold valve 410 having a tubular housing 412 with a flexible bladder 414 sealed to the housing 412. When the pressure is below the critical pressure, the blade 414 maintains the shape shown in FIG. 37A. In this way, the ball 416 is prevented from passing through the bladder 414, thereby preventing the flow of gas through the housing 412. Since the channel 418 communicates with the interior of the bladder 414, when the patient has created a vacuum greater than the threshold pressure, the bladder 414 moves to the position shown in FIG. 37B so that gas flows through the housing 412. To do it.

38 shows a threshold valve 420 with a tubular housing 422 having a breakable diaphragm 424. The diaphragm 424 is configured to rupture as shown by the dashed line when the critical vacuum is applied by the user.

39 shows a critical valve 420 having a tubular housing 422 and a valve member 430 pivotally connected to the housing 428. The valve member 430 resists the flow of gas through the housing 428 when in the closed position as shown in FIG. 39. Stop 432 prevents valve member 430 from opening when critical vacuum is generated by the user. The stop 432 is connected to the thin film 434 held in the chamber 436. Chamber 436 communicates with the interior of housing 428 by passage 438. In this way, when sufficient vacuum is generated, the stop 432 is raised to allow the valve member 430 to open. Conveniently, an outlet 440 may be provided to allow air to flow into the chamber 436 when the membrane 434 is moved upward. In addition, a spring 442 may be provided to move the valve member 430 to the open position when the stop 432 is raised.

40 shows a through valve critical valve 444 having a housing 446 and a valve member 448 disposed within the housing 446. Stop 450 holds valve member 448 in place until critical pressure is generated by the patient. When a threshold pressure is generated, the valve member 448 contracts as shown by the dashed line, allowing the valve member 448 to pass through the stop 450.

After the powder is extracted from the receptacle and aerosolized, various flow regulators may be used to limit the flow of gas flowing through the aerosolization apparatus into the user's lungs. Such flow regulators are arranged to limit the flow rate through the aerosolization device for a certain time to ensure that the flow rate of the aerosol moving anatomically useless volume through the air passage is sufficiently low.

41 schematically illustrates one embodiment of a flow regulator 460. The regulator 460 is configured to limit the flow of gas to less than about 15 L / min, more preferably less than about 10 L / min. Flow regulator 460 may be configured to increase with a vacuum generated by a user that is small at a low flow resistance vacuum. Conveniently, flow regulator 460 may be disposed in a flow path that is parallel to the receptacle containing the powder. In such a case, the flow regulator may provide a system flow resistance R that varies from about 0.1 (cm H ₂ O) ^1/2 per standard liter (SLM) to the resistance of the receptacle flow path. Alternatively, the flow controller may be arranged in line with the receptacle. In such a case, the system resistance R can vary from the resistance of the receptacle flow path to a resistance greater than 1.0 (cm H ₂ O) ^1/2 / SLM.

42-59 show various types of flow regulators that can be used in an aerosolization apparatus to regulate gas flow after the receptacle is opened. For example, FIG. 42A shows a flow regulator 462 having an L-shaped housing 464 with a flow channel 466. Shuttle 468 with skirt seal 470 can be slid within housing 464. Recovery spring 472 biases shuttle 468 to the position shown in FIG. 42A. As the flow rate through the housing 464 increases, the shuttle 468 moves within the housing 464 to compress the spring 472 and block the flow channel 466. In this method, the flow rate is limited to a predetermined ratio. If the flow rate is too excessive, channel 466 closes when shuttle 468 engages stop 474 as shown in FIG. 42B. When the flow stops, spring 472 moves shuttle 468 to the starting position.

FIG. 43 illustrates a flow regulator 476 that also includes a threshold valve similar to the configuration described above with respect to FIG. 28. The regulator 476 has a housing 478 with a tapered flow channel and a thin film 482 that acts as a critical valve in a manner similar to that described above. In FIG. 43, the ball 484 is pressed against the spring 486 by vacuum generated by the user through the thin film 482. As the vacuum increases, the spring 486 compresses as the ball 484 moves further into the channel 480 as shown by the dashed line. As a result, the flow path is limited, thereby limiting the flow of gas. The spring constant of the spring 486 can be adjusted to provide the desired flow control characteristics.

44A and 44B show flow regulator 488 with tubular housing 490 in which bellows 492 are disposed. Bellows 492 may be made of an elastomer configured to compress as the flow through housing 490 increases, as shown in FIG. 44A. As the bellows 492 is compressed, the flow path 494 through the bellows is reduced to limit the flow rate.

45 shows a flow regulator 496 having a tubular housing 498 in which the conical member 500 with the orifice 501 is slidably disposed. Restriction member 502 with flow channel 504 is also retained in housing 498. A spring 506 is disposed between the conical member 500 and the limiting member 502. As the flow rate through the orifice and the flow channel 504 increases, the spring 506 is compressed to further move the conical member 500 into the flow channel 504, whereby the gas passing through the housing 498. Restricts the flow of

46 shows a flow regulator having a tubular housing 510 having a flow channel 514 and a closed end 412 that allows gas to flow from the other housing 516 with flow channel 518 into the housing 510. 508 is shown. The spring 520 biases the housing 510 to the left as shown in FIG. 46. As the flow rate increases, the spring 520 extends to move the housing 510 to the right in FIG. 46. As such, flow channel 514 is limited by housing 516 to limit gas flow.

FIG. 47 shows a flow regulator 520 having a tubular housing 522 having a compartment 524 filled with an open cell foam 526. The open cell foam material limits and regulates the flow of gas through the housing 522 by using a vacuum applied to compress the foam to deflate the porous flow channel.

FIG. 48 shows a flow regulator 528 having a tubular housing 530 with a support 532 with multiple orifices 534. Umbrella member 536 is held by support 532 to limit gas flow through housing 530. Conveniently, the umbrella member 536 can be flipped in a similar manner as described in connection with FIGS. 43A and 43B and can also function as a threshold valve.

FIG. 49 shows a flow regulator 538 having a housing 540 with an inlet 542 and an outlet 544. The liquid 546 is disposed in the housing 540. As the gas flows through the housing 540, the gas creates bubbles in the liquid 546 that regulates the flow of gas through the housing 540.

50 shows a flow regulator 548 with a tubular housing 550 having a neck region 552. Shuttle 554 is maintained in housing 550 and forced into neck region 552 when the vacuum force increases. The force required to move the shuttle 554 is controlled by the spring 556. In this way, as the vacuum force increases, the flow path is limited to limit the flow rate through the housing 550.

FIG. 51 shows a flow regulator 556 having a tubular housing 558 having a spindle 560 slidable within the housing 558. The spring 562 biases the spindle 560 to the right as shown in FIG. 51 such that the flow path 564 of the spindle 560 is aligned with the flow path 566 in the housing 558. Thus, in the position shown in FIG. 51, gas can flow through the housing 558 by passing through the flow path 564 and the flow path 568 of the spindle 560. However, as the vacuum force increases, the spindle 560 moves to the left to limit the flow path 566, thereby limiting the flow of gas through the housing 558.

52 shows a flow regulator 570 having a tubular housing 572 with an inflatable cone 574. Cone 574 includes an orifice 576 and is configured such that when the flow rate is low as shown in FIG. 52, the gas flow not only passes through the orifice 576 but also passes around the cone 574. When the flow rate is increased, gas flow is only allowed through the orifice 576 because the cone expands to provide a seal for the housing 572.

53A and 53B illustrate a flow regulator 580 having an iris valve 582. One end 584 is fixed and the other end 586 is rotated to move the iris valve 582 to the position shown in FIG. 53B. In this way, the flow rate through the iris valve 582 can be adjusted.

54 shows a flow regulator 588 having a housing 590 having an outer ring 592 that is rotatable only in one direction as shown by the arrows. The outer ring 592 is pivotally connected to the housing 590 by a frictional connection that can be adjusted to regulate the amount of gas flow through the housing 590. As only rotatable in one direction, the outer ring 592 also serves as a check valve.

55A and 55B show flow regulator 594 with tubular housing 596 with pivot flap 598. Flap 598 is configured to close when subjected to high gas flow as shown in FIG. 55B to reduce the flow rate through housing 596.

Another type of flow regulator includes a valve comprised of a flexible elastomer, such as a silicone rubber, such as silicone rubber, which restricts flow to a desired flow rate while preventing flow in the opposite direction. Such valves can also reset themselves, eliminating the need for mechanical aids. Such valves include an orifice that allows the flow of air through the valve in response to an applied vacuum, and one or more shrinking walls surrounding the orifice to reduce the orifice area due to increased vacuum pressure levels and thus increase flow resistance. It includes. One feature of such a valve is that the manufacturing cost is relatively low. One particular example of such a valve is disclosed in US Pat. No. 5,655,520, the entire disclosure of which is incorporated herein by reference.

56A and 56B illustrate one embodiment of such a flow regulator 600. The flow regulator has an elastomer body 602 having a duckbill valve 604 that includes an orifice 606. In FIG. 56A, the flow rate is low and the orifice 606 is completely opened. When the flow rate is increased, the valve 604 begins to close as shown in FIG. 56B to limit the flow.

Another example of such a flow regulator is shown in FIGS. 57-59. In FIG. 57, the flow regulator 608 includes a duckbill valve 610 with an upper orifice 612. 58 shows a flow regulator 614 including a duckbill valve 616 with an orifice 618 extending from top to bottom. FIG. 59 shows a flow regulator 620 that includes a duckbill valve 622 with separate upper orifices 624 and side orifices 626.

After the flow rate through the aerosolization device is adjusted for a period of time, the aerosolization device may be configured to allow for increased flow rate. In this way, the user can fill the lungs with sufficient volume of air needed to transport the aerosol deep into the lungs. For example, following the adjustment of the flow rate, the aerosolization device may be configured to comfortably fill the lungs as the user continues to inhale through the device. Typically, a user can fill the lungs at a comfortable flow rate if the initial volume of about 500 mL is aspirated at a regular flow rate. This assumes that after 500 mL of intake air has passed the anatomical dead space in the lungs.

To provide such features, various timers or flow integrators may optionally be incorporated into the aerosolization apparatus of the present invention. Such flow integrators have one or more movable members that move based on the flow volume through the aerosolization apparatus. In this way, when the initial (adjusted) volume is sucked, the movable member can be sufficiently moved to open another gas channel to allow for increased gas flow. For example, the flow integrator may be an airfoil flap made from a film such as a polymer film having a thickness of 0.005 to 0.020 inches, and preferably has a viscoelastic or other time dependent reaction. Air flow above the airfoil flap causes lift in aerodynamics. The airfoil flap is configured to allow access to a parallel flow path after a predetermined volume of air flow at the top of the flap.

FIG. 60 schematically illustrates a through-flow flow integrator 630 configured to move based on flow velocity, where a low pressure drop is contemplated. The flow integrator 630 moves using the flow regulator described above based on the pressure difference between the atmosphere and the inlet, which can vary considerably even if the flow rate remains constant. One advantage of the flow integrator 630 is that it provides accurate volumetric measurements.

FIG. 61 schematically shows an integrator 632 in the form of diesel oil parallel to the main flow path. Optionally, integrator 632 may trigger a switch at the end of the movement to open parallel flow paths with low flow resistance.

62A and 62B show a flow integrator 634 in the form of a through shuttle having a tubular housing 636 and a shuttle 638 slidable within the housing 636. Conveniently, the skirt seal 640 provides a seal between the housing 636 and the shuttle 638 while allowing the shuttle 638 to slide. Stops 642 and 644 are also provided to limit the movement of the shuttle 638. In FIG. 62A, the shuttle 638 is in a closed position where the mainstream through the aerosolization device passes through the opening 646 of the shuttle 638, and parallel flow through the channel 648 is caused by the shuttle 638. It is stopped. Shuttle 638 moves through housing 636 in response to the velocity of gas flowing through housing 636. The traction force, and thus the speed at which the shuttle 638 moves, is proportional to the flow rate. As shown in FIG. 62B, shuttle 638 moves past channel 648 after a predetermined time, allowing increased flow to flow through housing 636.

FIG. 63 shows a flow integrator 650 having a tubular housing 652 through which main gas flow through the aerosolization apparatus passes. Within the housing 652 is an impeller 654 connected to the gear reducer 656. In turn, as shown in FIG. 64, the gear reducer 656 is connected to a cam 658 having a hole 660. The cam 658 is rotatable through a tubular housing 662 that provides a parallel flow path through the aerosolization device. In operation, the user provides gas flow through the housing 652 which inhales and rotates the impeller 654. In order, cam 658 is rotated through gear reducer 656. When cam 658 reaches a certain angle, hole 660 is aligned with housing 662 to open a parallel flow path for the pushed air.

As an alternative to impeller 654, outer ring 664 may be used as shown in FIG. 65. In such embodiments, the outer ring 664 may be connected to the gear reducer 656 in a manner similar to that described above.

66A and 66B show a flow integrator 666 with a tubular housing 668 having parallel flow paths 670. The main flow path 672 is connected to the housing 668. The opening 674 places the housing 668 and the flow path 672 in fluid communication. Within the housing 668 is arranged a shuttle having a skirt seal 678 that provides a seal between the shuttle 676 and the housing 668. A spring 680 is disposed between the housing 668 and the shuttle 676, and an umbrella valve 682 with a bleed hole 684 extends through the housing 668.

As shown in FIG. 66B, shuttle 676 inhibits parallel gas flow through flow path 670 when the user initially begins to inhale. Shuttle 676 moves under the action of the force of spring 680 attenuated by bleed hole 684 (or alternatively by controlled leaks around shuttle 676). The shuttle 676 moves faster when the pressure difference between the inlet side (with bleed hole 684) and the outlet side (with opening 674) increases due to the vacuum generated by the user. When shuttle 676 reaches the end of the path, parallel flow path 670 is opened for the air to be pushed. Thereafter, a reset rod 686 can be used to reset the shuttle 676 to the position shown in FIG. 66B.

FIG. 67 shows a flow integrator 690 with a tubular housing 692 serving as the main flow path. Brake system 694 with pivot brake arm 696 extends into housing 692. A brake pad 698 is coupled to the brake arm 696 as shown in FIG. 68. The integrator 690 also has a wheel 700 that moves through a tubular housing that acts as a parallel flow path for the pushed air. The wheel 700 includes a hole 703 that aligns with the housing 702 when the wheel 700 is at a particular angle. The brake arm 696 is elastically loaded relative to the wheel 700 by the spring 701. The wheel 700 is also connected to a trigger 704 that fits into the groove 706 of the brake arm 696.

To operate the integrator 690, the user winds up a spring (not shown) that rotates the wheel 700 at a constant speed when detached. When the user generates mainstream through the housing 692, the brake arm 696 pivots to separate the trigger 704 and the brake pad 698. The wheel 700 is then rotated at a constant speed until the hole 703 is aligned with the housing 702, thereby opening the parallel flow path for the air being pushed.

The critical valves, flow regulators, and optionally flow integrators of the present invention may be arranged in various forms within the aerosolization apparatus. For example, FIG. 69 illustrates an aerosolization system 710 with several components arranged in series. The aerosolization system 700 is continuously provided with an inlet 711, a critical valve 712, a flow regulator 714 in a penetrating form, a receptacle 718 holding a powdered medicine and an outlet 720. . The overall resistance of the receptacle 718 is configured to be less than or equal to the resistance of the rest of the system until the flow integrator 716 is opened. Conveniently, the order of the threshold valve 712 and the flow regulator 714 and the flow integrator 716 (if it is a through type integrator) may be interchanged. Alternatively, the flow integrator 716 may be a diesel diesel type integrator that may be parallel to the receptacle 718. Receptacle 718 may be last in the series to prevent medicament from stacking on other components. Conveniently, the threshold valve 712, the flow regulator 714, and the flow integrator 716 can be integrated into one mechanism.

FIG. 70 illustrates an aerosolization system 722 having an inlet 724, a threshold valve 726, a flow regulator 728, a flow integrator 732 in the form of diesel oil, and an outlet 734. Flow integrator 732 is arranged parallel to threshold valve 726 and flow regulator 728. In the system 722, the maximum system resistance may be less than or equal to the resistance of the receptacle 730. In this way, some users may achieve a flow rate of 10 L / min or more. Flow integrator 732 operates with a pressure difference between atmosphere and outlet 734. Conveniently, threshold valve 726 and flow regulator 728 may be integral.

FIG. 71 illustrates an aerosolization system 736 with an inlet 738, a critical valve 740, a flow integrator 742, a flow regulator 744, a receptacle 746 and an outlet 748. Doing. In the aerosolization system 736, the order of the threshold valve 740 and the flow integrator 742 may be varied. Also, the maximum system resistance may be less than or equal to the resistance of the receptacle 746. The use of a penetrating integrator provides a more accurate volumetric measurement because the integrator acts as a result of the flow rate through it. The aerosolization system 736 also allows integration of the threshold valve 740 and the flow regulator 744, or the flow integrator 742 and the flow regulator 744. In one aspect, the aerosolization system 736 opens without the flow integrator 742 limiting the flow spikes that occur after the threshold valve 740, so that the entire high flow rate passes through the receptacle 746 to disperse the powder. It may be configured to.

72-78 illustrate one particular embodiment of an aerosolization apparatus 750 incorporating a threshold valve, a flow regulator, and a flow integrator. The aerosolization device 750 has a housing 752, a door 754 pivoted to the housing 752 by a shaft 756, and a pivotable mouthpiece 758. As best shown in FIG. 73, the door 754 is openable so that the receptacle 760 (shown already open) can be inserted into the aerosolization apparatus 750. The aerosolization device 750 further includes an extraction tube 762 in communication with the mouthpiece 758 to allow the drug extracted from the receptacle 760 to pass through the mouthpiece 758. A grinder 764 is provided in the mouthpiece 758 that can grind any agglomerated powder extracted from the receptacle 760. Conveniently, the grinder 764 also serves as a shaft on which the mouthpiece 758 pivots. The extraction tube 762 is connected to the cutter 766 for puncturing the receptacle 760 when the door 754 is closed so that the drug can be extracted.

The door 754 incorporates a threshold valve 768 having a membrane 770 with an opening 772. When the threshold vacuum generated by the user is met or exceeded, the valve member 774 with the ball 776 can be moved through the opening 772. In operation, the user inhales in the passage 778 communicating with the right side of the membrane 770 and in the mouthpiece 758 generating a vacuum in the extraction tube 762. Once the threshold vacuum pressure is met or exceeded, the ball 776 passes through the opening 772 to allow outside air to enter the area 780 of the door 754 through an outlet (not shown). In this way, air flows through the receptacle 760 to extract the powdered medicament delivered to the mouthpiece 758. Conveniently, the aerosolization apparatus 750 further includes a cam 782 that moves the ball 780 to its original position through the opening 772 when the door 754 opens and closes to reset the valve.

The aerosolization apparatus 750 further includes a flow regulator 784 that restricts air flow through the extraction tube 762 at a predetermined flow rate. Flow regulator 784 has a tapered opening 786 into which the ball 780 retracts when the vacuum generated by the user increases. Spring 785 controls the amount of vacuum required to close the opening with ball 776. Therefore, if the flow rate becomes too large, the parallel flow path 788 leading to the extraction tube 762 is blocked by the ball 780. In this way, only the air passing through the extraction tube 762 must pass through the receptacle 760 as described above. This flow path has sufficient resistance so that the flow is limited to the desired speed. If the user does not generate enough vacuum to close the flow path 788, the air flow is allowed to pass through two parallel flow paths.

The aerosolization device 750 further includes a flow regulator 790 that can allow increased flow rate after a predetermined time so that the user can comfortably fill the lungs after the flow is adjusted for a particular time. Flow integrator 790 has a clutch septum 792 on which spool 794 rests. Spool 784 is deflected to rotate by torsion spring 796. In this way, when the diaphragm 792 is separated from the spool 794, the spool 794 aligns the opening (not shown) of the spool 794 with the opening 798 of the extraction tube 762 (see FIG. 76). Rotate until At this point, the atmosphere flows through the parallel flow path to the extraction tube 762 to allow the user to comfortably fill the lungs with air.

As described above, the diaphragm 792 is configured to descend to separate the spool 794 due to the vacuum generated in the flow path 788 when the user inhales in the mouthpiece 758. The rotational speed of the spool (and thus the time required to open the parallel flow path) is determined by the damping reservoir 800 containing damping grease. The fastening member 802 frictionally engages with the damping grease. Although not shown, the aerosolization apparatus 750 may include a reset lever that resets the spool 794 after use.

79-83 illustrate another embodiment of an aerosolization device 850 having a lower housing 852, an upper housing 854, and a rotatable mouthpiece 856. As best shown in FIG. 80, the lower housing 852 can be separated from the upper housing 854 so that the receptacle 858 containing the medicament can be inserted into the aerosolization device 850. Lower housing latch 855 is provided to limit movement of lower housing 852 relative to upper housing 854. The mouthpiece 856 is connected with a tube 860 having a cutting mechanism 862 for opening the receptacle 858 when the receptacle 858 is inserted to place the lower housing 852 near the upper housing 854. do.

A thin film 862 having an opening 864 is disposed across the lower housing 852. A latch 866 with a ball 868 extends through the opening 864. The hole 890 of the lower housing 852 is disposed below the latch 866. Such a configuration provides a threshold valve for the device 850. In this way, when the user inhales in the mouthpiece 856, a vacuum is created in the space above the tube 860 and the membrane 862. When the user generates sufficient vacuum, the ball 868 passes through the opening 864 of the membrane 862 so that outside air passes through the hole 890, through the opening 864, through the receptacle 858 and The aerosolized medicament is allowed to flow through the tube 860 exiting through the mouthpiece 856.

Once the medicament is aerosolized, a portion of the air flow through the aerosolization device 850 is adjusted to be below a predetermined rate through the use of an elastomeric duckbill valve 892. More specifically, the air can flow through two flow paths provided so that the flow rate is below a certain amount, that is, through the valve 892 and the receptacle 858. As the flow rate of air increases, valve 892 begins to close to block air flowing through this flow path. Thereafter, air can only pass through the receptacle 858, which provides sufficient resistance to limit the flow to the desired flow rate.

The cam 883 of the latch 866 is connected with a bypass diffuser 894 that engages the stop 896. The diffuser 894 is connected to a spring 897 and is also slidable in the bypass duckville valve 898. As the user continues to inhale in the mouthpiece 856, the cam 833 of the latch 866 moves the diffuser 894 away from the stop 896. This causes spring 897 to expand as shown in FIG. 82 to compress bellows 900 and to spread valve 898 that is closed in normal condition. In this way, after a predetermined time, the valve 898 opens to provide another flow path so that more atmosphere can flow through the aerosolization device 850 through the hole 890. In this way, the user can comfortably fill the lungs after initial drug delivery. The compression rate of the bellows 900 is controlled by filling the bellows with a known amount of air and providing a small orifice to the bellows 900. In this way, once the diffuser 894 is separated from the stop 896, the compression rate is controlled by the time required to pressurize the air out through the orifice.                 

84-87 illustrate another embodiment of an aerosolization device 910 having a lower housing 912, an intermediate housing 914, an upper housing 916, and a mouthpiece 918. The lower housing 912 is movable relative to the intermediate housing 914 so that the receptacle 920 containing the medicament can be inserted as shown in FIG. 85. The mouthpiece 918 is connected to a tube 922 configured to puncture the receptacle 920 to provide access to the medication.

The intermediate housing 914 includes a thin film 924 having an opening 926. The valve member 928 with the ball 930 is disposed within the lower housing 912 to act as a critical valve to ensure that sufficient vacuum is created by the user when initially inhaling the medicament. In operation, the user inhales in the mouthpiece 918 to generate a vacuum in the tube 922 and in the space above the membrane 924. Once sufficient vacuum is generated, the ball 930 passes through the opening 926 so that the atmosphere passes through the hole 932, through the opening 926, through the receptacle 920, through the tube 922 and to the mouthpiece. (918) Let it flow out. If so, the medication is extracted from the receptacle 920 and supplied to the user.

The aerosolization device 910 is also configured to regulate the flow rate of air passing through the device 910 after the ball 930 passes through the membrane 924. This is accomplished in part by the use of the elastomeric duckbill valve 934 of the upper housing 924. As the user continues to inhale, the atmosphere entering through the hole 932 also passes through the opening 926 and then through the valve 934. Thereafter, air moves out of mouthpiece 918 through opening 936 and opening 938. However, if the flow rate is too large, the valve 934 is closed to prevent air flow through this flow path. As a result, air can only flow through the receptacle 920 and the tube 922 which regulates the flow rate within a certain flow rate (due to the limited size of the receptacle and the tube) to allow the aerosolized drug to reach the user's lungs. .

After a certain time, the aerosolization device 910 is configured to allow increased flow of air through the device 910 so that the user can comfortably fill his lungs with air. This is accomplished by using a piston 940 which is connected to the upper housing 916 by a pair of rolling seals 942, 944. The piston 940 further includes a hole 946 that moves between the seals 942, 944 after a predetermined time. Upon reaching this position, the atmosphere flows out of the mouthpiece 918 through the hole 936, through the opening 932 and through the hole 946. In this way, an additional flow path is provided so that the user can comfortably fill his lungs after initial drug delivery.

The piston 940 is moved due to the pressure difference between the upper region 950 of the piston 940 and the lower region 952 of the piston 940. This pressure difference is caused by the vacuum created in the upper region 950 when the user starts to inhale due to the bleed hole 954 in communication with the upper region 950. The size of the bleed hole 954 is configured to control the resulting vacuum in the upper region 950 and thus the speed of upward movement of the piston 940.

Various techniques may be used to ensure that the user properly positions his mouth over the mouthpiece while using the aerosolization device of the present invention. For example, a lip guard may be provided on the mouthpiece to allow the user to place his lips near the lip guard. In another embodiment, the mouthpiece may comprise engagement means or other markings. Alternatively, one or more holes may be provided on the side of the mouthpiece. This hole must be able to be covered by the lips to create enough vacuum to operate the aerosolization device. As a further embodiment, the mouthpiece may have a circular to elliptical contour. The elliptical portion should be able to be covered by the patient's mouth so that sufficient vacuum can be created. Optionally, a tongue suppressor may also be used to suppress the user's tongue when inhaling in the mouthpiece.

Referring now to FIG. 88, an embodiment of a mouthpiece 1000 will be described. Mouthpiece 1000 has a tubular member 1002 having a distal end 1004 configured to connect to an aerosolization device and an open proximal end 1006. The cross-sectional contour of the distal end 1004 is circular, while the cross-sectional contour of the proximal end 1006 is curved or elliptical. In this method, the mouth should be placed over the mouthpiece 1000 until the user's lips reach the circular portion to create the vacuum needed to operate the aerosolization device. The mouth positioning device on another mouthpiece 1000 has a pair of holes 1008 that must be covered by the user's lips to generate the required vacuum. As another alternative, the mouthpiece 1000 may include an engagement mark 1010 for the user's front teeth. Similar engagement marks may be provided for the lower teeth of the user.

FIG. 89 illustrates another embodiment of a mouthpiece 1012 having a tubular member 1014 having a slidable distal end 1016 above the tubular extension 1018, which in turn is connected to the aerosolization device. . In this method, the user may adjust the distance between the proximal end 102 of the tubular member 1014 relative to the aerosolizing device. According to one embodiment, the device is ready for operation when the tubular extension 1018 is in the patient's mouth, and the patient presses the extension 1018 forward in the direction towards the device and thereby actuates the device. Applying force to extension 1018 as it prepares. The tubular member 1014 also includes a tongue suppressor 1022 that suppresses the user's tongue during inhalation to facilitate passage of the aerosolized powder past the patient's tongue into the lungs.

The devices and methods of the present invention can be used in both liquid or powdered pharmaceutical formulations. The amount of active agent in the formulation is the amount necessary to deliver an amount of active therapeutically effective agent to achieve the desired result. In fact, this amount will vary widely depending on the particular active agent, the severity of the condition, and the desired therapeutic effect. According to a preferred embodiment for administering powder formulations, active agents which must be delivered at a dose of 0.001 mg / day to 100 mg / day, preferably 0.01 mg / day to 50 mg / day, are generally practical for pulmonary delivery.

Powder formulations suitable for use in the present invention include dry powders and particles suspended or dissolved in the propellant. The powder formulation has a particle size selected to penetrate into the alveoli, that is, preferably a particle size of less than 10 μm mass median diameter (MMD), more preferably less than 7.5 μm, most preferably less than 5 μm, the diameter of which is Is usually 0.1 µm to 5 µm. The release of this powder is greater than 30%, usually greater than 40%, preferably greater than 50%, usually greater than 60%, and the particle size distribution of the aerosol is about 1.0 to 5.0 μm mass median aerodynamic diameter (MMAD) , Usually 1.5 to 4.5 μm MMAD, preferably 1.5 to 4.0 μm MMAD. These dry powders have a moisture content of about 10% by weight or less, usually about 5% by weight or less, preferably about 3% by weight or less. Such powders are disclosed in WO 95/24183, WO 96/32149, and WO 99/16419, which are incorporated herein by reference.

The receptacles of the present invention are conveniently configured to have perforated access leads that are perforated by one or more sharp structures when the aerosolization apparatus is operated. Examples of such receptacles are disclosed in US Pat. Nos. 5,740,754 and 5,785,049, all of which are incorporated herein by reference.

The present invention can utilize a variety of grinding instruments to grind the pharmaceutical formulation once the pharmaceutical formulation is extracted from the receptacle. For example, the flow path of the gas may be changed one or more times in the direction that causes the pharmaceutical formulation to hit the walls of the flow path in order to break up the formulation. The flow furnace may also include various shrinkages or restrictions that may cause the pharmaceutical formulation to hit the walls of the flow path in order to break the pharmaceutical formulation. As another example, the flowpath may include one or more forced parts or obstacles that serve to collide with the pharmaceutical formulation as it passes through the flowpath. According to a preferred embodiment, the diameter of the grinding mechanism is larger than the diameter of the flow path.

The present invention has been described in detail so as to clarify the understanding. However, it should be understood that certain changes and modifications may be made within the scope of the appended claims.

Claims (52)

As aerosolization method of pharmaceutical preparations, Placing a valve in the air passage leading to the lung to prevent the respiratory gas from flowing into the lung when the user attempts to inhale, and then when the vacuum actuating vaccum caused by the attempted inhalation is exceeded Allowing the breathing gas to flow into the lungs suddenly by opening the valve, Extracting the pharmaceutical formulation from the receptacle and placing the pharmaceutical formulation within the flow of breathing gas to use the flow of breathing gas to form an aerosol Including, The vacuum run threshold is in the range of 20 cm H ₂ O to 60 cm H ₂ O. The method of aerosolization of a pharmaceutical formulation according to claim 1 wherein the flow of the respiratory gas into the lungs is regulated. The method of claim 2, wherein the flow rate is adjusted to be less than 15 L / min. 3. The method of aerosolization of a pharmaceutical formulation according to claim 2, wherein the flow rate is sufficient to allow an inhaled volume in the range of 125 mL to 1.25 L. 3. The method of aerosolization of a pharmaceutical formulation according to claim 2, wherein the flow rate of the respiratory gas is limited by controlling the size of the air passage leading to the lung. 6. The method of aerosolization of a pharmaceutical formulation according to claim 5, wherein the size of the air passage is controlled by an elastomeric membrane having an opening and the size of the opening varies with flow rate. The method of claim 1, wherein the pharmaceutical formulation comprises a powdered medicament, further comprising using the flow of respiratory gas to deagglomerate the extracted powder. The method of claim 1, wherein the receptacle comprises a receptacle body having a chamber holding the pharmaceutical formulation, further comprising placing the receptacle in a position in communication with the air passage. The method of aerosolization of a pharmaceutical formulation according to claim 1 wherein the vacuum run threshold is in the range of 40 cm H ₂ O to 60 cm H ₂ O. The aerosolization of a pharmaceutical formulation according to claim 1 wherein the valve comprises a bistable member and the bistable member moves from a first stable position to a second stable position when the vacuum actuation threshold is exceeded. Way. The method of claim 1, wherein the pharmaceutical formulation is extracted downstream of the valve. The method of claim 1, wherein the pharmaceutical formulation is a powdered medicament. The method of aerosolization of a pharmaceutical formulation according to claim 1, wherein the pharmaceutical formulation is a liquid. In the aerosolization apparatus, A housing defining an air passage; A coupling mechanism configured to connect a receptacle containing a pharmaceutical formulation to the air passage; And Including a valve, The valve prevents breathing gas from flowing through the air passage until the vacuum actuation threshold, which is when the valve is open, is exceeded, and when the vibration actuation threshold is exceeded, the valve opens to breathe gas into the air passage. Allow to flow through and extracting the pharmaceutical formulation from the receptacle to form an aerosol, And said vacuum actuation threshold of said valve is in the range of 20 cm H ₂ O to 60 cm H ₂ O. 15. The aerosolization apparatus of claim 14, further comprising a regulator for adjusting the flow rate of respiratory gas through the air passage. 16. An aerosolization apparatus according to claim 15 wherein the regulator limits the flow rate to less than 15 L / min. 16. The aerosolization apparatus of claim 15, wherein the regulator comprises an elastomeric membrane that adjusts the size of the air passage. 15. The aerosolization apparatus of claim 14, further comprising a deaggglomeration mechanism disposed in the air passage for milling the extracted pharmaceutical formulation. 15. The aerosolization apparatus of claim 14 wherein the valve is configured to be disposed within the receptacle. 15. The aerosolization apparatus of claim 14 wherein the aerosolization apparatus is configured to removably receive the receptacle. 15. The aerosolization apparatus of a pharmaceutical formulation according to claim 14 wherein the vacuum actuation threshold is in the range of 40 cm H ₂ O to 60 cm H ₂ O. 15. The aerosolization apparatus of claim 14, wherein the valve comprises a bistable member and the bistable member moves from a first stable position to a second stable position when the vacuum actuation threshold is exceeded. 15. The aerosolization apparatus of claim 14, wherein the valve is positioned such that the pharmaceutical formulation is extracted downstream of the valve. The aerosolization apparatus of a pharmaceutical formulation according to claim 14 wherein the pharmaceutical formulation in the receptacle is a powdered medication. The aerosolization apparatus of a pharmaceutical formulation according to claim 14 wherein the pharmaceutical formulation in the receptacle is liquid. As aerosolization method of pharmaceutical preparations, When a user attempts to inhale, the valve is placed in an air passage leading to the lung to prevent the respiratory gas from flowing into the lungs, and then when the vacuum actuating vaccum caused by the attempted inhalation is exceeded. Opening the valve to allow breathing gas to flow into the lungs abruptly; Extracting the pharmaceutical formulation from the receptacle and placing the pharmaceutical formulation within the flow of breathing gas to use the flow of breathing gas to form an aerosol Including, The vacuum running threshold ranges from 20 cm H ₂ O to 60 cm H ₂ O, And the receptacle comprises a perforable portion over the chamber holding the pharmaceutical formulation and further comprises perforating the perforated portion to expose the pharmaceutical formulation. In the aerosolization apparatus, A housing defining an air passage, A coupling mechanism configured to connect a receptacle containing a pharmaceutical formulation to the air passage; Including a valve, The valve prevents breathing gas from flowing through the air passage until the vacuum actuation threshold, which is when the valve is open, is exceeded, and when the vacuum actuation threshold is exceeded, the valve opens to breathe gas into the air passage. Allow to flow through and extracting the pharmaceutical formulation from the receptacle to form an aerosol, The vacuum actuation threshold of the valve ranges from 20 cm H ₂ O to 60 cm H ₂ O, Wherein said aerosolization device comprises a member for perforating a perforated portion of said receptacle to expose said pharmaceutical formulation. In the aerosolization apparatus, A receptacle having a chamber with a pharmaceutical formulation and a critical valve; A housing defining an air passage, Connecting mechanism for positioning the valve across the air passage and for placing the pharmaceutical formulation in fluid communication with the air passage Wherein the threshold valve is configured to open when the vacuum actuation threshold is exceeded, allowing breathing gas to flow through the air passage and extracting the pharmaceutical formulation from the chamber to form an aerosol; Is in the range of 20 cm H ₂ O to 60 cm H ₂ O. The aerosolization device of claim 28 wherein the pharmaceutical formulation comprises a powdered medicament. The aerosolization device of claim 28 wherein the pharmaceutical formulation comprises a liquid medicament. 29. The aerosolization apparatus of claim 28, further comprising a conditioning system for regulating the flow of breathing gas through the air passage. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

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